It has long been known that the naturally-occurring semisynthetic opium alkaloids, or "opiates", manifest their pharmacologic effects both centrally and peripherally. The primary target sites for the former effects are the brain and the spinal cord. For example, morphine is used as an analgesic, to induce sleep in the presence of pain and to suppress cough. The major peripheral sites are located in the gastrointestinal tract. Thus, opiate agonists also inhibit gastric emptying and the propulsive motor activity of the intestine. The anti-diarrheal action of opiate analgesics such as morphine is a manifestation of this effect. Efforts to minimize the central nervous system (CNS) effects of opiates while retaining a useful level of activity in peripheral tissues have resulted in the preparation of quaternary derivatives of narcotic antagonists and agonists by addition of a second alkyl substituent on the ring nitrogen atom. See D. R. Brown et al., Neuropharmacology, 24, 181 (1985). However, while these compounds generally exhibit reduced penetration of the blood brain barrier, they also exhibit a substantially-lowered overall affinity for opiate receptors.
Therefore, a need exists for opiates which exhibit high levels of activity with respect to gastrointestinal tissue, without exhibiting substantial levels of access to the CNS. A need also exists for opiates with characteristically high levels of antidiarrheal activity which exhibit low levels of undesirable CNS effects such as drowsiness, lowered respiratory activity and addictive potential. A further need exists for gut-specific antagonist opiates which can selectively reverse the peripheral activity or protect against the peripheral activity of agonist narcotics.